Chronic rhinosinusitis (CRS) is estimated to affect 13% of the US population, with annual health care direct costs of nearly $10 billion per year, yet there are few effective therapies for CRS. Detection of Staphylococcus aureus and/or Pseudomonas aeruginosa biofilm in the sinus mucosa is associated with severe CRS presentation. Healthy cells that line the nasal passages normally emit significant levels of nitric oxide (NO), a potent and natural antimicrobial molecule that stimulates mucociliary clearance and reduces bacterial biofilm formation. Reduced levels of NO in the exhaled nasal breath of CRS patients suggest that boosting local NO concentrations within the sinuses may be quite beneficial. In Phase I of this project, NOTA Laboratories, LLC, clearly demonstrated that a naturally occurring and inexpensive NO releasing agent, S-nitrosoglutathione (GSNO), can be incorporated into a typical saline/bicarbonate sinus rinse solution and generate adequate levels of NO to significantly reduce levels of live bacteria counts for two biofilm forming CRS microbes (S. aureus and P. aeruginosa). In these experiments, the bacterial biofilms were grown on the surface of human upper airway epithelial cells. We further demonstrated that the levels of GSNO and concomitant NO released do not harm the underlying human cells, as assessed by monitoring the levels of a toxicity-associated cytokine (IL-8). In addition, NOTA demonstrated that the release rates of NO from GSNO can be enhanced by the presence of ascorbate (Asc; vitamin C) and that the resulting powder formulations of GSNO/Asc can be stored for more than 6 months (at 37 C) while retaining >80% of their NO release capability. Via Phase II SBIR funding, NOTA will: 1) Further optimize the concentration of the GSNO/Asc mixture within an isotonic NaCl/NaHCO3/EDTA solution and frequency of application for the in vitro disruption of S. aureus and P. aeruginosa biofilms formed on human upper airway epithelial cells over 3 d test periods; 2) Explore a commercial packaging process (in polymer film lined aluminum pouches) and test the resulting 1-year stability of a dry packaged GSNO/Asc/NaCl/NaHCO3/EDTA mixed powder that will be reconstituted in plastic sinus flush bottles with 240 mL of pure water immediately before use by patients; 3) Conduct animal studies in rabbits to determine if NOTA's reconstituted RSNO/Asc/NaCl/NaHCO3/EDTA formulation, given as an aerosol spray twice daily over a 7 d period, significantly decreases bacterial counts in the sinus cavities of infected rabbits (with CRS) vs. controls (only NaCl/NaHCO3/EDTA); and 4) Begin the regulatory process by obtaining expert assessments of the role of the FDA in approval of the new GSNO formulations as a potential over-the-counter product for the CRS market. The completion of these efforts during Phase II will enable NOTA to plan the first human subject clinical trials at the University of Michigan Sinus Center as part of Phase III studies.
Chronic rhinosinusitis (CRS) affects an estimated 13% of the US population, with direct costs of nearly $10 billion annually. The inadequacy of current therapies presents an unmet need of immense commercial opportunity. CRS patients are known to have reduced nitric oxide (NO) levels in their sinus cavities, which contribute to the formation of microbial biofilm that cannot be eradicated by antibiotics. Phase 1 research has demonstrated the effectiveness of NOTA Laboratories' new sinonasal spray/rinse solution containing S-nitrosoglutathione (GSNO) that releases low levels of NO capable of reducing microbial biofilm grown on the surface of human epithelial cells without exhibiting any toxicity toward the human cells. In Phase II, further development of this product is proposed, including additional optimization of a dry powder formulation, commercial packaging studies, animal experiments, and exploring the regulatory issues required for the eventual launch of a new product that will have a profound impact on the prevention/treatment of CRS for many patients. !
